Cancer-killing pill that 'annihilates' tumors now being tested on humans

04 Aug 2023
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Phase 1PROTACsClinical Result
The drug was developed by researchers at the City of Hope, one of the largest cancer research and treatment organizations in the US, over a 20-year period.
The AOH1996 molecule targets a cancerous variant of PCNA, a protein critical to DNA replication and repair of enlarging tumors.
It has shown to be effective in preclinical research treating cells derived from breast, prostate, brain, ovarian, cervical, skin and lung cancers
The research, published in the journal Cell Chemical Biology, tested the treatment across over 70 cancer cell lines. The results found that AOH1996 selectively kills cancer cells by ‘disrupting the normal cell reproductive cycle’.
It targets transcription replication conflicts, which occur when mechanisms responsible for gene expression and genome duplication collide.​
The investigational therapy prevented cells with damaged DNA from dividing in G2/M phase and from making a copy of faulty DNA in S phase. As a result, AOH1996 caused cancer cell death (apoptosis), but it did not interrupt the reproductive cycle of healthy stem cells.
However, while early results are promising, the research so far has only been conducted with cell and animal models – with a phase 1 human trial currently underway.
Professor Linda Malkas, senior author of the new drug study, said: "PCNA is like a major airline terminal hub containing multiple plane gates. Data suggests PCNA is uniquely altered in cancer cells, and this fact allowed us to design a drug that targeted only the form of PCNA in cancer cells."
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“Our cancer-killing pill is like a snowstorm that closes a key airline hub, shutting down all flights in and out only in planes carrying cancer cells. Results have been promising. AOH1996 can suppress tumor growth as a monotherapy or combination treatment in cell and animal models without resulting in toxicity. The investigational chemotherapeutic is currently in a phase 1 clinical trial in humans at City of Hope."
Professor Long Gu, lead author of the study, added: “No one has ever targeted PCNA as a therapeutic because it was viewed as 'undruggable,' but clearly City of Hope was able to develop an investigational medicine for a challenging protein target.
“We discovered that PCNA is one of the potential causes of increased nucleic acid replication errors in cancer cells. Now that we know the problem area and can inhibit it, we will dig deeper to understand the process to develop more personalized, targeted cancer medicines."
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